Catalase activity deficiency sensitizes multidrug-resistant Mycobacterium tuberculosis to the ATP synthase inhibitor bedaquiline

Boatema Ofori-Anyinam, Meagan Hamblin, Miranda L. Coldren, Barry Li, Gautam Mereddy, Mustafa Shaikh, Avi Shah, Courtney Grady, Navpreet Ranu, Sean Lu, Paul C. Blainey, Shuyi Ma, James J. Collins and Jason H. Yang ()
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Boatema Ofori-Anyinam: Rutgers New Jersey Medical School
Meagan Hamblin: Broad Institute of MIT and Harvard
Miranda L. Coldren: Seattle Children’s Research Institute
Barry Li: Rutgers New Jersey Medical School
Gautam Mereddy: Rutgers New Jersey Medical School
Mustafa Shaikh: Rutgers New Jersey Medical School
Avi Shah: Rutgers New Jersey Medical School
Courtney Grady: Rutgers New Jersey Medical School
Navpreet Ranu: Broad Institute of MIT and Harvard
Sean Lu: Rutgers New Jersey Medical School
Paul C. Blainey: Broad Institute of MIT and Harvard
Shuyi Ma: Seattle Children’s Research Institute
James J. Collins: Broad Institute of MIT and Harvard
Jason H. Yang: Rutgers New Jersey Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Multidrug-resistant tuberculosis (MDR-TB), defined as resistance to the first-line drugs isoniazid and rifampin, is a growing source of global mortality and threatens global control of tuberculosis disease. The diarylquinoline bedaquiline has recently emerged as a highly efficacious drug against MDR-TB and kills Mycobacterium tuberculosis by inhibiting mycobacterial ATP synthase. However, the mechanisms underlying bedaquiline’s efficacy against MDR-TB remain unknown. Here we investigate bedaquiline hyper-susceptibility in drug-resistant Mycobacterium tuberculosis using systems biology approaches. We discovered that MDR clinical isolates are commonly sensitized to bedaquiline. This hypersensitization is caused by several physiological changes induced by deficient catalase activity. These include enhanced accumulation of reactive oxygen species, increased susceptibility to DNA damage, induction of sensitizing transcriptional programs, and metabolic repression of several biosynthetic pathways. In this work we demonstrate how resistance-associated changes in bacterial physiology can mechanistically induce collateral antimicrobial drug sensitivity and reveal druggable vulnerabilities in antimicrobial resistant pathogens.

Date: 2024
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DOI: 10.1038/s41467-024-53933-8

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